Angioplasty is a technique whereby an artery clogged by an atherosclerotic plaque and/or thrombus is mechanically cleared. Angioplasty procedures are much less invasive and much less traumatic than conventional alternatives such as coronary bypass surgery and have gained widespread acceptance as a means of obtaining dilation or clearance of arteries. In conventional angioplasty procedures, a small balloon-tipped catheter is introduced into an artery, often using a guide wire or a catheter tube in which a collapsed balloon may be positioned at one or more points of arterial stenosis, i.e. narrowing. These balloon and catheter assemblies are often referred to as coronary balloon dilation catheters. In many cases, the catheters are designed to permit continued distal dye injections through the balloon to permit visual verification of proper approach to a lesion or other area in which the procedure is to be employed.
However, it is also well known that angioplasty procedures involve risks of both local and systemic thromboembolic effects, tearing of an arterial wall, and restenosis. As used herein, restenosis refers to a worsening of lumenal stenosis in an artery which is characterized by a hyperplasia of cells of the arterial wall, resulting from an injury to the arterial wall which is a direct consequence of the angioplastic procedure. In this respect, restenosis differs notably from an occlusion of the artery by an arterial atherosclerotic plaque or occlusion by thrombus. In fact, restenosis within a few months (3-6 months) after angioplasty occurs in about 25 to about 55% of patients so treated, depending on a number of variables including, but not limited to age, sex, previous angioplastic procedures, extent of the narrowing, number of arteries involved, smoking, nutrition, diabetes mellitus and activity patterns.
While not wishing to be bound by any particular theory, restenosis may result from the body's natural recuperative response to any internal injury. Specifically, restenosis might be explained as the uncontrolled accumulation of macrophage cells and platelets generally involved in the natural healing processes of the body. Macrophages are amoeboid cells and engulf tissue debris, microbes and foreign particles. Platelets are fragments of a type of bone marrow cell and do not have a nucleus; they are involved principally in blood coagulation. These cells and platelets accumulate in the area injured by angioplasty and tend to form a protective barrier to cover the inner lining of the arterial site which has had fibrotic, calcific and fatty debris pushed into the wall by the dilated balloon. The macrophage cells and platelets also begin an oxidative metabolism of arachidonic acid to form a variety of compounds including prostaglandins, thromboxane A.sub.2, leucotrienes, and related oxidation products. Some of these compounds are chemo-attractants and cause platelets, macrophage cells and white blood cells to accumulate in the arterial wall at the angioplasty site. Once activated through the oxidative metabolism of arachidonic acid, the macrophage cells and platelets produce additional products including cytokines, platelet-derived growth factor, and macrophage-derived growth factor (PDGF and MDGF respectively). These cytokines and factors act to stimulate not only the further accumulation of platelets, white blood cells and macrophage cells but also the cell division of smooth muscle cells and fibroblasts. Certain prostaglandins, as well as PDGF and MDGF, are potent activators of cell mitosis and division. If left unchecked, eventual occlusion, i.e. restenosis, results in 3-6 months.
There is additional evidence to suggest that these restenosis processes may be mediated by a highly reactive class of compounds known as free radicals. Restenosis is therefore believed to involve an increase in concentrations of free radicals, beyond the level present in undamaged tissues. Free radicals contain an unpaired electron in an outer orbital and are consequently unstable and attack other molecules in order to obtain electrons to complete their electron orbitals. The hyperplasia (cell division of smooth muscle cells and fibroblasts) which characterizes restenosis may be triggered through a sequence of events initiated by the destructive free radical moieties generated by injury to the arterial wall during the angioplasty procedure. Traumatic injuries are known to cause destructive free radicals. These free radical moities may include such molecules as perioxidized lipids and oxidized cholesterol molecules which may be generated during the metabolic conversion of arachidonic acid and other polyunsaturated lipids as previously described. Furthermore, cholesterol is more rapidly oxidized in the presence of lipid peroxides, as formed from arachidonic acid and other polyunsaturates. In addition, lipid peroxide free radicals formed in response to vascular injury increase thromboxane A2 synthesis by platelets. Thromboxane A2 is a powerful vasoconstrictor which also stimulates platelet adherence and aggregation. These phenomena, acting in concert, may explain restenosis.
It has been common to use injections of heparin and various known calcium blockers as well as such compounds as aspirin, persantine, and intravenous dextran in an attempt to minimize the complications often attendant to such angioplasty.
U.S. Pat. No. 4,820,732, issued in the name of Shell et al., suggests the application of prostaglandin E-1 to reduce dysfunction in an angioplasty procedure. Certain prostaglandin compounds have been suggested for their effectiveness in providing antiplatelet effects and antithrombotic effects.
The remaining procedures for the prevention and/or treatment of restenosis involve the use of mechanical/surgical procedures such as intravascular stenting, a procedure in which an expandable metallic sleeve is placed within the artery after angioplasty. Unfortunately this method places a patient in higher risk for acute coronary occlusion, in addition to the risks that additional surgical procedures pose.
The antioxidant properties of the tripeptide glutathione are known in the art, yet its use in human treatment has been limited to the treatment of viral infections, hepatic disorders, pernicious anemia, heavy metal poisoning, and as an adjunct to cancer chemotherapy, See, for example, U.S. Pat. Nos. 3,146,165, 4,689,347, 4,229,468 and 4,762,705. Glutathione has also been used experimentally by aerosol instillation in patients with AIDS, to suppress recurrence of severe pneumonias (Buhl, et al., The Lancet, Dec. 2, 1989 pp. 1294-1298). It has also been used in cosmetic preparations and for weight loss as disclosed in U.S. Pat. Nos. 4,229,468, 3,984,569 and 4,460,978 and as a food or cosmetic preservative. See also U.S. Pat. Nos. 4,009,264, 4,751,285, 4,761,399 and U.S. Pat. No. 5,023,235.
Vitamin C (ascorbic acid), Vitamin E (alpha tocopherol), beta carotene, (precursor to Vitamin A) and the B vitamins have been used in various multi-vitamin compositions to promote general health. Vitamins of these general classes have also been used in combination with other compounds in the treatment of rheumatic diseases, for the temporary stimulation of urine production, for desensitizing the gastro intestinal tract from food allergies, for the treatment of liver disorders, for treatment of cuts, burns and abrasions, for the treatment of inflammatory changes of the bronchial mucosa, and for relief in pain as has been disclosed in U.S. Pat. Nos. 4,619,829, 4,760,080, 4,721,716, 4,761,399, 4,784842, 4,606,920, and 4,650,688. Vitamins have also been used in food preparations as a method for preventing rancidification.
Multivitamin and mineral supplements including bioflavonids, L-glutathione and L-cysteine have been suggested for use in preventing cancer, preventing cardiovascular and immunological disorders and for increasing longevity. See WO 91/11117. The use of dietary antioxidants together with a methionine compound to ameliorate inflammatory symptoms of respiratory disease has also been suggested. U.S. Pat. No. 4,927,850.
Despite the dramatic advances in cardiac surgery and care realized in recent years, there remains a need for effective, inexpensive, non-surgical techniques for the prevention and treatment of restenosis. In the United States, approximately 300,000 angioplasties were carried out in 1989, and a significant number of patients will restenose.